JPH07108897B2 - Novel proline derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel proline derivative having prolyl endopeptidase inhibitory activity, and is used in the field of medicine.

[0002]

2. Description of the Related Art With the advent of an aging society, the problem of medical care for the elderly has been emphasized, and senile dementia has become a serious social problem. In order to respond to this, various developments of new medicines have been made. However, conventional therapeutic agents for amnesia and dementia have many ambiguous expressions such as cerebral circulation improving agents, cerebral metabolism stimulating agents or cerebral function improving agents due to their mechanism of action, and they are all motivational disorders, emotional disorders, and behavioral abnormalities. Although it is effective in improving peripheral symptoms, the effect is not always clear for core symptoms of dementia such as memory impairment and disorientation, and the development of a drug that brings more reliable action is desired. There is.

On the other hand, prolyl endopeptidase (Pr
oryl endopeptidase; EC, 3.
4.21.26) is an enzyme that acts on a peptide containing proline, and is known to specifically cleave the carboxyl group side of proline. This enzyme acts on neurotransmitters such as thyrotropin-releasing hormone (TRH), substance P, and neurotensin, as well as learning,
It is also known to act on vasopressin, which is said to be involved in the process of memory, to decompose and inactivate them.

From these findings, if compounds having inhibitory activity against this enzyme can be obtained, these compounds are agents that suppress the decomposition and inactivation of vasopressin and the like and directly act on the core symptoms of dementia. As a result, it is expected that it can be applied to the prevention and treatment of amnesia or dementia (biochemistry,
55 , 831 (1983): Jpn Jpn Pharmacol. 89 , 243.
(1987): J. Pharmacobio-Dy
n. , 10 , 730 (1987)), and TRH,
By suppressing the degradation and inactivation of substance P, hormones such as neurotensin, and neurotransmitters, it is expected to be effective in improving the symptoms of diseases caused by the degradation and inactivation of these substances. To be done. From this point of view, various developments regarding prolyl endopeptidase inhibitors have been conventionally made, and, for example, JP-A-60-18.
No. 8317, No. 62-148467, No. 64-42475, or No. 2-28149.
Various proline derivatives are described and disclosed in the publications and the like.

[0005]

Therefore, the present inventors have found that
Based on the above findings, as a result of intensive studies to find a compound having an amino acid, particularly a proline residue, as a fragment and specifically and strongly inhibiting the action of prolyl endopeptidase, the result of the above-mentioned general formula [1] It was found that the novel proline derivative shown has a specific and potent prolyl endopeptidase inhibitory activity, and completed the present invention.

[0006]

That is, the present invention provides the following general formula [1]

[Chemical 5]

[Chemical 6] (However, k is an integer of 1 to 3, R ¹ is a hydrogen atom or a lower alkyl group), W is

[Chemical 7] Or CH ₃ — (wherein R ² represents a hydrogen atom, a halogen atom or a lower alkoxy group), and X is —S—, —S.
_{O -, - SO 2 -,} - O- or -NH- and, R represents

[Chemical 8] Or a lower alkyl group (wherein 1 is an integer of 0 to 3,
Y and Z are the same or different and each is a hydrogen atom, a halogen atom,
It means a lower alkyl group which may be substituted with a fluorine atom, an amino group, a nitro group, a hydroxyl group or a lower alkoxy group.
Y and Z may be combined to form a saturated or unsaturated 5- and 6-membered ring), and n is an integer of 1 to 6]. Another object of the present invention is to provide a pharmaceutical composition containing the novel proline derivative [1] as an active ingredient and useful as a prolyl endopeptidase inhibitor.

The definitions of various substituents used in the present specification are as follows. The "halogen atom" is chlorine, bromine, fluorine or iodine. "Lower alkyl group"
Means a straight or branched hydrocarbon chain having 1 to 5 carbon atoms, and specifically, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and the like. The "lower alkoxy group" is methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, tert-butoxy group and the like. The novel proline derivative represented by the general formula [1] according to the present invention can be produced, for example, according to the reaction steps shown below.

[0008]

[Chemical 9]

[Chemical 10] Each of the above reaction steps will be further described. The symbols A, B, W, X, R, k and n have the same meanings as described above.

Reaction (A) The compound represented by the general formula [2] is reacted with a sulfurylide derived from trimethylsulfonium iodide or trimethyloxysulfonium iodide in the presence of a strong base to give the compound represented by the general formula [3]. To obtain the epoxide shown. In this reaction, for example, n-butyllithium or sodium hydride-dimethyl sulfoxide is used in an anhydrous inert solvent such as tetrahydrofuran, dioxane, or hexane to produce a sulfyllide from the above sulfonium salt, and then the compound [2] is used. It is achieved by reacting with. The reaction temperature is -70 ° C to reflux temperature, preferably -10 ° C to room temperature.

Reaction (B) The compound represented by the general formula [3] is prepared by reacting the compound represented by the general formula HX-R (X) in the presence or absence of a base in a suitable solvent.
= S, O, NH) and the compound [4]
The alcohol compound represented by the general formula [5] is obtained. Specifically, for example, the reaction with HS-R in which X is a sulfur atom is carried out in the presence of a tertiary amine such as triethylamine or N-methylmorpholine in the presence of methanol,
It is carried out in a solvent such as dioxane or dimethylformamide. In the case of reaction with HO-R in which X is an oxygen atom, sodium methoxide in methanol is used, or
Alternatively, HO-R is converted to anion OR using sodium hydride in a solvent such as dioxane or dimethylformamide, and then reacted with [3]. H ₂ where X is NH
The reaction with NR is carried out in a solvent such as methanol or dioxane. The reaction temperature is room temperature to reflux temperature in each case.

Reaction (C) General formula [5] or

The t-butoxycarbonyl group (Boc group) which is the amino-protecting group of the intermediate represented by [9] is removed according to a known method, and this is subjected to a condensation reaction with the compound represented by the formula [6] to obtain a compound [7] and [1
0] is obtained. Removal of the Boc group, which is an amino protecting group, can be carried out by using the formula [5] or

The intermediate represented by [9] is prepared by a known method using hydrobromic acid / acetic acid, hydrochloric acid / dioxane, formic acid, hydrochloric acid / acetic acid, trifluoroacetic acid or the like at −30 ° C.
It can be removed by acid treatment at a temperature of up to 70 ° C, preferably 0 ° C to 30 ° C. Next, the de-Boc derivative thus obtained is subjected to a condensation reaction with the compound [6] by a conventional method to obtain the amino acid derivative [7] or [10]. A method known per se can be adopted for this peptide formation reaction. Examples of methods that can be usually used include a method using N, N′-dicyclohexylcarbodiimide (DCC) as a condensing agent, an active ester method, and a mixed acid anhydride method. The reaction is carried out in an inert solvent at 0 ° C to under heating. As a suitable solvent, chloroform, diethyl ether, dimethylformamide, ethyl acetate, dichloromethane, tetrahydrofuran or the like can be used. In the active ester method, the above compound [6] is reacted with p-nitrophenol, thiophenol, p-nitrothiophenol, N-hydroxysuccinimide, etc. in the presence of DCC in an inert solvent to prepare an active ester (for example, , An ester with N-hydroxysuccinimide), which is isolated or is not isolated, and is further reacted with the de-Boc derivative described above at 0 ° C. to 40 ° C. in an inert solvent to form a peptide bond. Is. In the mixed acid anhydride method, the compound [6] and an acid halide (eg, pivaloyl chloride, tosyl chloride, oxalyl chloride) in the presence of a tertiary amine (eg, pyridine or triethylamine) in an inert solvent are used. ) Or an acid derivative (eg, ethyl chloroformate, isobutyl chloroformate) at 0 ° C. to 40 ° C. to form a mixed acid anhydride, and the mixed acid anhydride is further mixed with the above-mentioned Boc derivative at 0 ° C. to 40 ° C. It is reacted at ℃ to form a peptide bond. In addition, the DCC method is carried out in the presence or absence of the above-mentioned tertiary amine such as triethylamine in an inert solvent, or a suitable additive (for example, 1-hydroxybenzotriazole (HOBt),
Under the condition that N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB) is added or not added, DCC is used as a condensing agent to react the de-Boc product with [6] to obtain the desired product. It forms a peptide bond.

Reaction (D) The final objective [1] is obtained by oxidizing the alcohol compound represented by the general formula [7], [8] or [11] with an appropriate oxidizing agent. This reaction is carried out, for example, in an inert solvent such as benzene, methylene chloride or dimethylformamide at 0 ° C to reflux temperature, preferably 0 ° C to room temperature,
In the presence or absence of molecular sieves, pyridinium chlorochromate or pyridinium dichromate is used, or in an inert solvent such as methylene chloride, -80 ° C to room temperature, preferably -80 ° C to 0.
The presence of pyridine, trifluoroacetic acid, dimethylsulfoxide at 0 ° C in the presence of oxalyl chloride and triethylamine, with dimethylsulfoxide, or in the presence or absence of an inert solvent (such as benzene) at 0 ° C to room temperature. Sulfur trioxide-pyridine complex in the presence of a tertiary amine such as triethylamine and dimethylsulfoxide at −10 ° C. to room temperature in the presence of DCC or in the presence or absence of an inert solvent (for example, benzene). Is achieved by using

Reaction (E) Of the compounds represented by the general formula [7], a compound in which X is a sulfur atom is oxidized with a peracid such as m-chloroperbenzoic acid to obtain the compound represented by the general formula [8]. To obtain a sulfoxide form and a sulfone form. Specifically, in an inert solvent such as methylene chloride, chloroform or benzene, -2
By using 1 equivalent or 2 equivalents of m-chloroperbenzoic acid at 0 ° C to reflux temperature, preferably 0 ° C to room temperature, a sulfoxide compound or a sulfone compound can be obtained.

Reaction (F) The compound represented by the general formula [5] wherein X is NH is subjected to an amino protecting group R ^{3 by} a method known in peptide chemistry.
Introduce the compound

[9] is obtained. Although various kinds of amino protecting groups R ³ can be considered, the following reaction (

[9] → [10]) must be stable to acid treatment for de-Boc deoxidization, and examples include acyl-type protecting groups such as formyl group and trifluoroacetyl group, and urethane-type protecting groups. -Fluorenylmethyloxycarbonyl group, methylsulfonylethyloxycarbonyl group and the like. The introduction of these protecting groups can be achieved by a known method (“Basics and Experiments of Peptide Synthesis”, Izumiya et al., Maruzen). For example, the introduction of a trifluoroacetyl group is carried out by reacting with trifluoroacetic acid ethyl ester in a solvent such as methanol in the presence of a tertiary amine such as triethylamine at 0 ° C. to room temperature, preferably room temperature. In this reaction, R ³ may be introduced after protecting the free hydroxyl group with an appropriate protecting group in advance, if necessary.

Reaction (G) The compound [11] is obtained by removing the amino protecting group R ³ of the compound represented by the general formula [10]. The method for removing the amino-protecting group R ³ may vary depending on the kind of the protecting group, but a method known in peptide chemistry can be used. To be done. For example, the removal of the trifluoroacetyl group is carried out in a solvent such as methanol using potassium carbonate, sodium carbonate, ammonia or the like as a base at 0 ° C. to reflux temperature, preferably room temperature.

Next, a known or novel intermediate compound represented by the above general formula [6] will be described. Intermediate compound Q
-COOH is more specifically represented by the following general formula _{W- (CH 2) n -A-} CO-B-COOH ( wherein, A, B, W, n is as defined above), not available commercially In that case, for example, it can be produced by the following method. The reaction _{W- (CH 2) n -A-} CO-Y + H-B-COOMe ─ → W- (CH 2) n -A-CO-B-COOMe ─ → W- (CH 2) n -A-CO- B-COOH reaction _{W- (CH 2) n -A-} H + V-CO-B-COOMe ─ → W- (CH 2) n -A-CO-B-COOMe ─ → W- (CH 2) n -A -CO-B-COOH (In the formula, V represents a chlorine atom or a hydroxyl group.
Although methyl ester was used in the reaction, it is not limited to this and, for example, benzyl ester can also be used. In particular, in the above reaction, A is an oxygen atom or a single bond and B is

[Chemical 11] The reaction is such that A is -NH- or -CONH- and B is

[Chemical 12] Or - _{(CH 2) k} - is an effective method in the case of. These reactions will be described in more detail below.

Reaction An amino compound represented by the general formula H-B-COOMe is
In a solvent such as methylene chloride, chloroform, dioxane, or water, in the presence of a tertiary amine such as triethylamine or N-methylmorpholine, or sodium hydroxide at 0 ° C to room temperature, the compound represented by the general formula W- (CH ₂ ) _n -A-CO- By reacting it with a compound represented by Cl or using the peptide bond-forming reaction detailed in the above reaction (C).
- _{(CH 2)} is reacted with n -A-CO-OH. By a conventional method a compound represented by the general formula _{W- (CH 2) n -A-} CO-B-COOMe which then obtained, sodium hydroxide, using a base such as lithium hydroxide, 0 ° C. to hydrolysis at room temperature To do.

Reaction An amino (or amide) compound represented by the general formula W- (CH ₂ ) _n -A-H is treated with triethylamine and N in a solvent such as methylene chloride, chloroform, dioxane and water.
-In the presence of a tertiary amine such as methylmorpholine or sodium hydroxide at 0 ° C to room temperature, the general formula Cl-CO
-B-COOMe is reacted with an acid chloride represented by the formula-HO-CO-B-COOM by using the peptide bond-forming reaction detailed in the above-mentioned reaction (C).
React with a carboxylic acid represented by e. Then the resulting formula _{W- (CH 2) n -A-} CO-B-COOMe
The compound represented by the formula (wherein R ⁵ is a suitable amino protecting group) is hydrolyzed in the same manner as in the case of the reaction. Next, in the above, compound [7] and compound [10] are respectively compound [5] or compound

Although it is prepared by subjecting [9] to the condensation reaction with compound [6], it may be carried out stepwise as follows. That, B is - _{(CH 2)} k -,

[Chemical 13] In other cases, as shown in the reaction (K), the compound represented by the general formula R ⁵ −
A compound represented by the general formula [17] by subjecting a compound represented by B-COOH (R ⁵ is a suitable amino protecting group) to a condensation reaction with the compound [5] in the same manner as in the case of the above reaction (C). To get Then, as shown in the reaction (L), the amino protecting group R ⁵ of the compound [17] is removed by a known method, and then the compound of the general formula W- (CH ₂ ) _n -A-H is used.
(When A is O, NH, CONH) or the general formula W-
Target compound [7] by reacting with a compound represented by (CH ₂ ) _n —COOH (when A is a single bond)
Can be obtained. In the former case, for example, W-
(CH ₂ ) _n -A-H is reacted with phosgene, diphosgene, carbonyldiimidazole or the like in a suitable solvent such as dioxane or tetrahydrofuran in the presence of a tertiary amine such as triethylamine at -20 ° C to room temperature. Then, it is achieved by reacting with a deprotected form of compound [17]. If necessary, it may be carried out after protecting the free hydroxyl group of compound [17] with an appropriate protecting group. When A in the latter is a single bond, deprotection of the compound [17] using the method described in the above reaction (C), by the condensation reaction of the W- (CH _{2) n} -COOH To be achieved. On the other hand, B is - _{(CH 2)} k -,

[Chemical 14] In the case of, as shown in the reaction (M), the compound represented by the general formula R ⁶ —O
A compound represented by —CO—B—COOH (wherein R ₆ is a suitable carbonyl protecting group) is subjected to a condensation reaction with compound [5] in the same manner as in the case of the above reaction (C) to give compound [18].
To get Then, as shown in reaction (N), the present compound [1
After removing the carbonyl protecting group R ⁶ of 8] by a conventional method,
Formula W- (CH 2) by performing the reaction with a compound represented by n _-A-H to give a compound of interest (7). Specifically W- _{(CH 2)} a conventional manner by esterification of using _{n -OH, W- (CH 2)} n -N
After the free carboxylic acid obtained by the amide bond formation reaction described in the above reaction (C) using H ₂ or the deprotection (R ⁶ ) of compound [18] is introduced into an acid chloride, active ester or the like by a conventional method. W- is achieved by carrying out the reaction with _{(CH 2)} n -NH _2. If necessary, it may be carried out after protecting the free hydroxyl group of the compound [18] with an appropriate protecting group. Also with respect to compounds Preparation of [10], B is - _{(CH 2)} k -,

[Chemical 15] Otherwise, the compound

From [9], the compound represented by the general formula [19] can be prepared in the same manner as in the above reaction (K), and then the reaction (L) can be carried out in the same manner as above to prepare the target compound [10]. it can. Also, B is-(CH
₂ ) _k- ,

[Chemical 16] In case of

Compound [10] can be prepared by subjecting [9] to the above reaction (M) to give compound [20], and then performing reaction (N) in the same manner as above.

Isolation and purification of the thus-obtained compound represented by the general formula [1] from the reaction mixture is carried out by using any means commonly used in the field of synthetic organic chemistry. It can be isolated and purified by methods such as column chromatography, solvent extraction, recrystallization and the like. Isolation and purification may be carried out for each reaction or after completion of some reactions. The above-mentioned series of compounds each have 1 to 3 asymmetric centers in the molecule. In the present invention, the configuration of each asymmetric center is either R or S, or a mixture thereof. May be. Each optically active substance can be obtained by using an optically active compound as a starting material, or by purifying the obtained diastereomer mixture by a method such as column chromatography or recrystallization.

The following general formula [1]

[Chemical 17] The optically active sulfinyl compound represented by can be produced according to the steps shown below.

[Chemical 18] Each of the above reaction steps will be further described. Here, the symbols A, B, W, R and n are the same as above, and the reactions (C), (D), (K), (L), (M) and (N) are as described above. Is.

Reaction (H) The compound represented by the general formula [12] is prepared by the method described in the literature (P. Pitchen et. Al., J. Am. Ch.
em. Soc. , 106 , 8188-8193 (198).
4); H. Zhao et. al. , Tetrah
edron, 43 , 5135-5144 (1987), etc.) to give a compound of general formula [13].
To obtain the optically active sulfoxide.
This reaction is carried out in the presence of titanium tetraisopropoxide, optically active diethyl tartrate and water in a solvent such as methylene chloride or 1,2-dichloroethane at 0 ° C.
Hereinafter, it is preferably carried out at -40 ° C to -20 ° C using t-butyl hydroperoxide or cumene hydroperoxide.

Reaction (J) An optically active sulfoxide represented by the general formula [13] is treated with a base to give an ylide, which is condensed with an ester or aldehyde represented by the general formula [14] or [15], respectively. To obtain an optically active sulfinyl compound represented by the general formula [1] or [16]. This reaction is carried out, for example, by reacting an optically active sulfoxide [13] with TH.
The corresponding ylide is formed with a base such as n-butyllithium or lithium diisopropylamide at a reaction temperature of −78 ° C. to room temperature, preferably 0 ° C. or lower in an inert organic solvent such as F or dioxane, and then the ester is formed. This is accomplished by adding [14] or aldehyde [15] and conducting the condensation reaction at -78 ° C to room temperature, preferably at -78 ° C to -20 ° C.

When the compound of the present invention is used as a medicine, it is usually administered systemically or locally, orally or parenterally. The dose varies depending on age, weight, symptoms, therapeutic effect, administration method, etc., but is usually once per adult per dose.
It is orally administered once to several times a day in the range of mg to 500 mg, or 0.2 mg to 100 once per adult.
It is administered parenterally in the range of mg once to several times a day. The compound of the present invention is used in the form of a solid composition for oral administration, a liquid composition or an injection for parenteral administration, suppository and the like. Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. In such solid compositions one or more active substances are used in admixture with at least one inert diluent,
If necessary, an excipient, a binder, a lubricant, a disintegrant, a solubilizing agent, a stabilizer and the like may be contained. Tablets or pills
If necessary, it may be coated with a film of a gastric or enteric substance. Capsules include hard capsules and soft capsules. Liquid compositions for oral administration include solutions, emulsions, suspensions, syrups and elixirs. In such a liquid composition, a commonly used inert diluent is contained, and other than that,
It may contain an auxiliary agent such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, and a preservative. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. In such an injection, one or more active substances are mixed with at least one inert aqueous diluent or an inert non-aqueous diluent and used, and if necessary, further preserved. Auxiliary agents such as agents, wetting agents, emulsifiers, dispersants, stabilizers and solubilizing agents may be contained. These are usually sterilized by filtration (bacterial retention filter, etc.), blending of a bactericide or gamma irradiation, or after these treatments, a solid composition is prepared by a method such as lyophilization, and sterilized immediately before use. Used by adding water or a sterile diluent for injection.

EXAMPLES The present invention will be described in more detail below with reference to examples. The abbreviations used in the examples have the following meanings. DMF dimethylformamide DMSO dimethyl sulfoxide THF tetrahydrofuran HOBt 1-hydroxybenzotriazole DCC N, N′-dicyclohexylcarbodiimide ¹ H NMR Broton nuclear magnetic resonance spectrum CI-MS chemical ionization mass spectrometry spectrum FAB-MS fast atom bombardment mass spectrometry spectrum EI-MS Electron impact ionization mass spectrometry spectrum

Example 1 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-[(phenylthio) acetyl] pyrrolidine (Compound 1) A) (2S) -1- (t-butoxycarbonyl) -2-
(1,2-Epoxyethyl) pyrrolidine DMSO (20 ml) was added to sodium hydride (Na content 60%, 1.55 g), and the mixture was stirred at 70 ° C for 1 hr. The reaction solution was returned to room temperature, THF (20 ml) was added, the temperature was adjusted to -5 ° C., and a DMSO (30 ml) solution of trimethylsulfonium iodide (7.90 g) was added dropwise over 3 minutes. After stirring for 1 minute, t-butoxycarbonyl-L-prolinal (5.13 g) in THF (15 m
l) The solvent was added quickly and then stirred at room temperature for 1 hour.
The reaction solution was poured into ice water (300 ml) and extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) and (2S) -1- (t-butoxycarbonyl) -2-
Two diastereomers of (1,2-evoxyethyl) pyrrolidine, 3.12 g of low polar compound and 1.28 of high polar compound.
g was obtained (the steric structure of both epoxy moieties is undecided). In the following reaction, a low polar substance was used.

B) (2S) -1- (t-butoxycarbonyl) -2- [1-hydroxy-2- (phenylthio)
Ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2-
(1,2-Epoxyethyl) pyrrolidine (3.00 g)
To a methanol (100 ml) solution of was added thiophenol (1.5 ml) and triethylamine (2.0 ml), and the mixture was stirred under reflux for 2 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and (2S) -1- (t-butoxycarbonyl) -2- [1-hydroxy-2- (Phenylthio) ethyl] pyrrolidine (4.14 g) was obtained.

C) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-2- (phenylthio) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- [1
-Hydroxy-2- (phenylthio) ethyl] pyrrolidine (4.90 g) in 4N hydrochloric acid-dioxane (57 ml)
Was added and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating and drying the reaction solution was dissolved in DMF (100 ml), and the known N-benzyloxycarbonyl-L-proline (3.7
9 g), N-methylmorpholine (1.54 g) and HO
Bt (3.08g) was added. After cooling the reaction solution to -25 ° C, DCC (3.13 g) was added, and the reaction solution was stirred from -25 ° C to 0 ° C for 3 hours and then at room temperature for 16 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), (2S) -1-
(N-benzyloxycarbonyl-L-prolyl) -2
-[1-Hydroxy-2- (phenylthio) ethyl] pyrrolidine (6.56 g) was obtained.

D) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(phenylthio)
Acetyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (phenylthio) ethyl] pyrrolidine (908 mg) was added to DMSO (3
ml) and benzene (3 ml), pyridine (162 μl), trifluoroacetic acid (78 μl) and DCC (1.24 g) were sequentially added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate (50 ml) was added to the reaction solution, then a solution of oxalic acid (540 mg) in methanol (5 ml) was added, and the mixture was stirred for 30 minutes. Water (50 ml) was added to the reaction solution,
The precipitated dicyclohexylurea was filtered off. 1 filtrate
It was washed successively with N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(phenylthio) acetyl] pyrrolidine (714 mg) was added. Obtained (Table 1
reference).

Example 2 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-[(phenylsulfinyl) acetyl] pyrrolidine (Compound 2) A) (2S) -1- (N-benzyloxycarbonyl-
L-prolyl) -2- [1-hydroxy-2- (phenylsulfinyl) ethyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-prepared in C) of Example 1 [1-hydroxy-2- (phenylthio) ethyl] pyrrolidine (9
M-Chloroperbenzoic acid (380 mg) was added to a methylene chloride (30 ml) solution of 08 mg), and the mixture was stirred for 2 hours under ice cooling. The reaction mixture was diluted with chloroform and ice-cooled 10%
The extract was washed successively with sodium sulfite, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-2- (phenylsulfinyl). Ethyl] pyrrolidine (895 mg) was obtained.

B) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(phenylsulfinyl) acetyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (phenylsulfinyl) ethyl] pyrrolidine (850 mg) was subjected to DMSO-DCC oxidation in the same manner as in D) of Example 1 to give (2S) -1- ( N-benzyloxycarbonyl-L-prolyl) -2-[(phenylsulfinyl) acetyl] pyrrolidine (672 mg) was obtained (Table 1
reference).

Example 3 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-[(phenylsulfonyl) acetyl]
Pyrrolidine (Compound 3) A) (2S) -1- (N-benzyloxycarbonyl-
L-prolyl) -2- [1-hydroxy-2- (phenylsulfonyl) ethyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-prepared in C) of Example 1 [1-hydroxy-2- (phenylthio) ethyl] pyrrolidine (5
To a solution of 16 mg) in methylene chloride (30 ml) was added m-chloroperbenzoic acid (440 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was treated and purified in the same manner as in A) of Example 2 to obtain (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-2-
(Phenylsulfonyl) ethyl] pyrrolidine (540m
g) was obtained.

B) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(phenylsulfonyl) acetyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (phenylsulfonyl) ethyl] pyrrolidine (500 mg) was subjected to DMSO-DCC oxidation as in D) of Example 1 to give (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(phenylsulfonyl)
Acetyl] pyrrolidine (412 mg) was obtained (see Table 1).

Example 4 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- (phenoxyacetyl) pyrrolidine (Compound 4) A) (2S) -1- (t-butoxycarbonyl) -2-
(1-Hydroxy-2-phenoxyethyl) pyrrolidine of (2S) -1- (t-butoxycarbonyl) -2- (1,2-epoxyethyl) pyrrolidine (1.50 g) prepared in A) of Example 1 Phenol (1.50 g) and sodium methoxide (3) in a methanol (30 ml) solution.
80 mg) was added, and the mixture was refluxed with stirring for 16 hours. The reaction mixture was concentrated, the residue was dissolved in ether, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate),
(2S) -1- (t-butoxycarbonyl) -2- (1
-Hydroxy-2-phenoxyethyl) pyrrolidine (1.10 g) was obtained.

B) (2S) -1- (N-benzyloxycarbonyl-L-brolyl) -2- (1-hydroxy-)
2-phenoxyethyl) pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- (1
4N Hydrochloric acid-dioxane (16 ml) was added to -hydroxy-2-phenoxyethyl) pyrrolidine (1.10 g), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentrating and drying the reaction solution was dissolved in DMF (10 ml), and a known N-
Benzyloxycarbonyl-L-proline (850m
g), N-methylmorpholine (0.38 ml) and HO
Bt (0.68g) was added. The reaction solution was cooled to -25 ° C, DCC (0.72 g) was added, and the mixture was stirred at -25 ° C to 0 ° C for 3 hr, and then at room temperature for 12 hr. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- (1-
Hydroxy-2-phenoxyethyl) pyrrolidine (34
0 mg) was obtained.

C) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- (phenoxyacetyl) pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- (1-hydroxy-2-phenoxyethyl) pyrrolidine (393 mg) was subjected to DMSO-DCC oxidation in the same manner as in D) of Example 1 to give (2
S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- (phenoxyacetyl) pyrrolidine (32
8 mg) was obtained (see Table 1).

Example 5 (2S) -1- {N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-prolyl} -2-[(phenylsulfinyl) acetyl] pyrrolidine (Compound 5) A) N
-[(2-oxo-1-pyrrolidinyl) acetyl] -L
-Proline methyl ester L-proline methyl ester hydrochloride (8.28 g) in a DMF (100 ml) solution under ice cooling, N-methylmorpholine (5.50 ml), (2-oxo-1-pyrrolidinyl) acetic acid (7. 15 g) and HOBt (10.12 g)
Was added. The mixture was cooled to −25 ° C. and DCC (10.
32 g) was added and the mixture was stirred at room temperature for 16 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-proline methyl ester (12.94 g).

B) N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-proline N-[(2-oxo-1-pyrrolidinyl) acetyl]-
A 2N sodium hydroxide solution (12 ml) was added dropwise to a solution of L-proline methyl ester (5.06 g) in methanol (40 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The pH of the liquid was adjusted to 5 by adding 3N hydrochloric acid to the reaction liquid under ice cooling.
The reaction solution was concentrated to dryness, suspended in chloroform, and filtered. The filtrate was concentrated to give N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-proline (4.28 g).

C) (2S) -2- [1-hydroxy-2
-(Phenylthio) ethyl] -1- {N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-prolyl} pyrrolidine (2S) -1- (t-butoxycarbonyl) prepared in B) of Example 1. ) -2- [1-Hydroxy-2- (phenylthio) ethyl] pyrrolidine (2.62 g) was added with 4N hydrochloric acid-dioxane (40 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and dried, and the resulting residue was added to DMF (20
ml), N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-proline (1.95 g), N-methylmorpholine (0.9 ml), and HOBt (1.
31 g) was added. After cooling the reaction solution to -30 ° C, DCC
(1.68 g) was added, and the mixture was stirred at -30 ° C to 0 ° C for 3 hr, and then at room temperature for 16 hr. The reaction solution was used as C in Example 1).
Treated and purified in the same manner as in (2S) -2
-[1-hydroxy-2- (phenylthio) ethyl]-
1- {N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-prolyl} pyrrolidine (2.95 g) was obtained.

D) (2S) -2- [1-hydroxy-2
-(Phenylsulfinyl) ethyl] -1- {N-
[(2-oxo-1-pyrrolidinyl) acetyl] -L-
Prolyl} pyrrolidine (2S) -2- [1-hydroxy-2- (phenylthio) ethyl] -1- {N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-prolyl} pyrrolidine (2.
81 g) in methylene chloride (15 ml) under ice cooling,
m-Chloroperbenzoic acid (1.09 g) was added and stirred for 2 hours. After treating the reaction solution in the same manner as in Example 2 A), the residue was purified by silica gel column chromatography to obtain (2S) -2- [1-hydroxy-2- (phenylsulfinyl) ethyl] -1. -{N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-prolyl} pyrrolidine (2.63 g) was obtained.

E) (2S) -1- {N-[(2-oxo-1-pyrrolidinyl) acetyl] -L-prolyl} -2
-[(Phenylsulfinyl) acetyl] pyrrolidine (2S) -2- [1-hydroxy-2- (phenylsulfinyl) ethyl] -1- {N-[(2-oxo-1-
Pyrrolidinyl) acetyl] -L-prolyl} pyrrolidine (938 mg) was subjected to DMSO-DCC oxidation in the same way as in D) of Example 1 to give (2S) -1-
{N-[(2-oxo-1-pyrrolidinyl) acetyl]
-L-Prolyl} -2-[(phenylsulfinyl) acetyl] pyrrolidine (817 mg) was obtained (see Table 2).

Example 6 (2S) -1- [4- (4-chlorobenzylamino)-
4-oxobutyryl] -2-[(phenylsulfinyl) acetyl] pyrrolidine (Compound 6) A) (2S) -1- [4- (4-chlorobenzylamino) -4-oxobutyryl] -2- [1-hydroxy-
2- (Phenylthio) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- [1-hydroxy-2- (phenylthio) ethyl] pyrrolidine (3.28 g) prepared in B) of Example 1. 4N hydrochloric acid-dioxane (25 ml) was added to and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and dried, and the resulting residue was added to DMF (20
ml), and known 4- (4-chlorobenzylamino) -4-oxobutyric acid (2.46 g), N-methylmorpholine (1.2 ml) and HOBt (1.64 g) were added. After cooling the reaction solution to -25 ° C, DCC (2.09
g) was added, and the mixture was stirred at -25 ° C to 0 ° C for 3 hr, and then at room temperature for 16 hr. The reaction mixture was treated and purified in the same manner as in the case of C) in Example 1 to obtain (2S) -1- [4- (4-chlorobenzylamino) -4-oxobutyryl] -2- [1-
Hydroxy-2- (phenylthio) ethyl] pyrrolidine (3.75 g) was obtained.

B) (2S) -1- [4- (4-chlorobenzylamino) -4-oxobutyryl] -2- [1-hydroxy-2- (phenylsulfinyl) ethyl] pyrrolidine (2S) -1- [ 4- (4-chlorobenzylamino)-
4-oxobutyryl] -2- [1-hydroxy-2-
(Phenylthio) ethyl] pyrrolidine (3.75 g)
Was oxidized with 1.1 equivalents of m-chloroperbenzoic acid in methylene chloride in the same manner as in Example 2, A),
(2S) -1- [4- (4-chlorobenzylamino)-
4-oxobutyryl] -2- [1-hydroxy-2-
(Phenylsulfinyl) ethyl] pyrrolidine (3.7
0 g) was obtained.

C) (2S) -1- [4- (4-chlorobenzylamino) -4-oxobutyryl] -2-[(phenylsulfinyl) acetyl] pyrrolidine (2S) -1- [4- (4-chloro) Benzylamino)-
4-oxobutyryl] -2- [1-hydroxy-2-
(Phenylsulfinyl) ethyl] pyrrolidine (1.0
9 g) is treated with DMSO in the same manner as in D) of Example 1.
Subjected to DCC oxidation to (2S) -1- [4- (4-chlorobenzylamino) -4-oxobutyryl] -2-
[(Phenylsulfinyl) acetyl] pyrrolidine (9
74 mg) was obtained (see Table 2).

Example 7 (2S) -1- [N- (4-phenylbutyryl) -L-
Prolyl] -2-[(phenylsulfinyl) acetyl] pyrrolidine (Compound 7) A) N- (4-phenylbutyryl) -L-proline benzyl ester L-proline benzyl ester hydrochloride (7.37 g)
In methylene chloride (80 ml) under ice-cooling with N-methylmorpholine (3.4 ml) and 4-phenylbutyric acid (5.
02g) was added. After cooling to -25 ° C, DCC (6.3
1 g) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was treated and purified in the same manner as in the case of A) of Example 5 to obtain N-
(4-Phenylbutyryl) -L-proline benzyl ester (9.42 g) was obtained.

B) N- (4-phenylbutyryl) -L-
Proline N- (4-phenylbutyryl) -L-proline benzyl ester (9.31 g) in 99% methanol (100
ml) solution, 10% Pd-C (0.90 g) was added,
The mixture was stirred under a hydrogen stream at room temperature for 2 hours. The catalyst was filtered off using Celite, and the filtrate was concentrated to give N- (4-phenylbutyryl) -L-proline (6.26 g).

C) (2S) -2- [1-hydroxy-2
-(Phenylthio) ethyl] -1- [N- (4-phenylbutyryl) -L-prolyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- [prepared in B) of Example 1 4N hydrochloric acid-dioxane (23 ml) was added to 1-hydroxy-2- (phenylthio) ethyl] pyrrolidine (3.05 g), and the mixture was stirred at room temperature for 0.5 hr. The residue obtained by concentrating and drying the reaction solution is DMF.
Dissolve in (18 ml), N- (4-phenylbutyryl)
-L-Proline (2.65 g), N-methylmorpholine (1.2 ml) and HOBt (1.88 g) were added. The reaction mixture was cooled to -25 ° C, DCC (1.95 g) was added, and the mixture was stirred at -25 ° C to 0 ° C for 2 hr and at room temperature for 14 hr. The reaction solution was treated and purified in the same manner as in the case of C) of Example 1 to obtain (2S) -2- [1-hydroxy-2-
(Phenylthio) ethyl] -1- [N- (4-phenylbutyryl) -L-prolyl] pyrrolidine (2.45 g)
Got

D) (2S) -2- [1-hydroxy-2
-(Phenylsulfinyl) ethyl] -1- [N- (4
-Phenylbutyryl) -L-prolyl] pyrrolidine (2S) -2- [1-hydroxy-2- (phenylthio) ethyl] -1- [N- (4-phenylbutyryl)-
L-Prolyl] pyrrolidine (1.25 g) was oxidized in methylene chloride (9 ml) with 1.1 equivalents of m-chloroperbenzoic acid in the same manner as in Example 2, A),
(2S) -2- [1-hydroxy-2- (phenylsulfinyl) ethyl] -1- [N- (4-phenylbutyryl) -L-prolyl] pyrrolidine (1.18 g) was obtained.

E) (2S) -1- [N- (4-phenylbutyryl) -L-brolyl] -2-[(phenylsulfinyl) acetyl] pyrrolidine (2S) -2- [1-hydroxy-2-] (Phenylsulfinyl) ethyl] -1- [N- (4-phenylbutyryl) -L-prolyl] pyrrolidine (1.07 g) was subjected to DMSO-DCC oxidation in the same manner as in Example 1, D). Then, (2S) -1- [N- (4-phenylbutyryl) -L-prolyl] -2-[(phenylsulfinyl) acetyl] pyrrolidine (0.89 g) was obtained (Table 2).
reference).

Example 8 (2S) -1- [N- (benzyloxycarbonyl) glycyl] -2-[(phenylsulfinyl) acetyl]
Pyrrolidine (Compound 8) A) (2S) -1- [N- (benzyloxycarbonyl) glycyl] -2- [1-hydroxy-2- (phenylthio) ethyl] pyrrolidine Prepared in Example 1B) (2S). ) -1- (t-Butoxycarbonyl) -2- [1-hydroxy-2- (phenylthio) ethyl] pyrrolidine (2.65 g) was added with 4N hydrochloric acid-dioxane (20 ml), and the mixture was stirred at room temperature for 0.5 hours. . The residue obtained by concentrating and drying the reaction solution is DMF.
It was dissolved in (15 ml) and known N- (benzyloxycarbonyl) glycine (1.71 g), N-methylmorpholine (0.9 ml) and HOBt (1.33 g) were added. After cooling the reaction solution to -25 ° C, DCC (1.70 g)
Was added at −25 ° C. to 0 ° C. for 2 hours, then at room temperature for 14 hours.
Stir for hours. The reaction mixture was treated and purified in the same manner as in the case of C) in Example 1 to obtain (2S) -1- [N- (benzyloxycarbonyl) glycyl] -2- [1-hydroxy-
2- (phenylthio) ethyl] pyrrolidine (3.06
g) was obtained.

B) (2S) -1- [N- (benzyloxycarbonyl) glycyl] -2- [1-hydroxy-2
-(Phenylsulfinyl) ethyl] pyrrolidine (2S) -1- [N- (benzyloxycarbonyl) glycyl] -2- [1-hydroxy-2- (phenylthio) ethyl] pyrrolidine (1.32 g) from Example 2 Oxidation with 1.1 equivalents of m-chloroperbenzoic acid in methylene chloride (10 ml) as in A),
(2S) -1- [N- (benzyloxycarbonyl) glycyl] -2- [1-hydroxy-2- (phenylsulfinyl) ethyl] pyrrolidine (1.35 g) was obtained.

C) (2S) -1- [N- (benzyloxycarbonyl) glycyl] -2-[(phenylsulfinyl) acetyl] pyrrolidine (2S) -1- [N- (benzyloxycarbonyl) glycyl] -2 -[1-Hydroxy-2- (phenylsulfinyl) ethyl] pyrrolidine (1.30 g) was subjected to DMSO-DCC oxidation in the same manner as in Example 1 D) to give (2S) -1- [N- (Benzyloxycarbonyl) glycyl] -2-[(phenylsulfinyl) acetyl] pyrrolidine (0.94 g) was obtained (see Table 2).

Example 9 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-[(4-methoxyphenylsulfinyl) acetyl] pyrrolidine (Compound 9) A) (2S) -1- (t-butoxycarbonyl) -2-
[1-hydroxy-2- (4-methoxyphenylthio)
Ethyl] pyrrolidine 4- (4) was added to a solution of (2S) -1- (t-butoxycarbonyl) -2- (1,2-epoxyethyl) pyrrolidine (1.57 g) obtained in A) of Example 1 in methanol (50 ml).
Methoxythiophenol (1.0 ml) and triethylamine (1.0 ml) were added, and the mixture was stirred under reflux for 1.5 hr.
The residue obtained by concentrating the reaction solution was added to ice water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was recrystallized from a mixed solution of hexane-ethyl acetate to give the title compound as colorless needles (2.16 g).
Got

B) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-
2- (4-Methoxyphenylthio) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- [1
4N Hydrochloric acid-dioxane (15 ml) was added to -hydroxy-2- (4-methoxyphenylthio) ethyl] pyrrolidine (2.02 g), and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated and dried, the residue obtained was dissolved in DMF (15 ml), and the known N was added in the same manner as in the case of C) of Example 1.
-Benzyloxycarbonyl-L-proline (1.42
Condensation with g) gave the title compound (2.51 g). C) (2S) -1- (N-benzyloxycarbonyl-
L-prolyl) -2- [1-hydroxy-2- (4-methoxyphenylsulfinyl) ethyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (4-methoxyphenylthio) ethyl] pyrrolidine (1.51 g) in methylene chloride in the same manner as in A) of Example 2.
Oxidation with 1.1 equivalents of m-chloroperbenzoic acid gave the title compound (984 mg).

D) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(4-methoxyphenylsulfinyl) acetyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L) −
Prolyl) -2- [1-hydroxy-2- (4-methoxyphenylsulfinyl) ethyl] pyrrolidine (901
mg) in the same manner as in D) of Example 1 with DMSO
-DCC oxidation gave the title compound (652 mg) (see Table 3).

Example 10 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-[(4-nitrophenylsulfinyl) acetyl] pyrrolidine (Compound 10) A) (2S) -1- (t-butoxycarbonyl) -2-
[1-Hydroxy-2- (4-nitrophenylthio) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- (1,2-epoxyethyl) pyrrolidine obtained in A) of Example 1 To a solution of (1.39 g) in methanol (50 ml) 4-
Nitrothiophenol (1.21 g) and triethylamine (0.91 ml) were added, and the mixture was stirred under reflux for 2 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain the title compound (1.85 g).

B) (2S) -1- (N-Benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-
2- (4-Nitrophenylthio) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- [1
4N Hydrochloric acid-dioxane (20 ml) was added to -hydroxy-2- (4-nitrophenylthio) ethyl] pyrrolidine (1.64 g), and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated and dried, the residue obtained was dissolved in DMF (12 ml), and the known N was added in the same manner as in the case of C) of Example 1.
-Benzyloxycarbonyl-L-proline (1.10
Condensation with g) gave the title compound (2.03 g). C) (2S) -1- (N-benzyloxycarbonyl-
L-prolyl) -2- [1-hydroxy-2- (4-nitrophenylsulfinyl) ethyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (4-nitrophenylthio) ethyl] pyrrolidine (1.50 g)
Oxidation in methylene chloride with 1.1 equivalents of m-chloroperbenzoic acid as in Example 2 A) gave the title compound (894 mg).

D) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(4-nitrophenylsulfinyl) acetyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L) −
Prolyl) -2- [1-hydroxy-2- (4-nitrophenylsulfinyl) ethyl] pyrrolidine (883m
g) in the same manner as in D) of Example 1
Subjected to DCC oxidation to give the title compound (673 mg) (see Table 3).

Example 11 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-[(isopropylsulfinyl) acetyl] pyrrolidine (Compound 11) A) (2S) -1- (t-butoxycarbonyl) -2-
[1-hydroxy-2- (isopropylthio) ethyl]
Pyrrolidine A solution of (2S) -1- (t-butoxycarbonyl) -2- (1,2-epoxyethyl) pyrrolidine (2.11 g) obtained in A) of Example 1 in methanol (100 ml) was added with isopropyl mercaptan (0. (.93 ml) and triethylamine (1.39 ml) were added and the mixture was stirred under reflux for 2 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain the title compound (1.66 g).

B) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-
2- (Isopropylthio) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- [1
-Hydroxy-2- (isopropylthio) ethyl] pyrrolidine (1.68 g) in 4N hydrochloric acid-dioxane (25 m
1) was added, and the mixture was stirred at room temperature for 0.5 hours. The residue obtained by concentrating and drying the reaction solution was dissolved in DMF (12 ml),
The title compound (2.08 g) was obtained by condensation with known N-benzyloxycarbonyl-L-proline (1.46 g) in the same manner as in C) of Example 1.

C) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-
2- (isopropylsulfinyl) ethyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (isopropylthio) ethyl] pyrrolidine (1.61 g) was treated with 1.1 equivalents of m-chloro in methylene chloride in the same manner as in A) of Example 2. Oxidation with perbenzoic acid gave the title compound (1.40g).

D) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(isopropylsulfinyl) acetyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (isopropylsulfinyl) ethyl] pyrrolidine (1.34g)
In the same manner as in D) of Example 1
Subjected to C oxidation to give the title compound (502 mg) (Table 3
reference).

Example 12 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-{[(S) -phenylsulfinyl]
Acetyl} pyrrolidine (Compound 12) A) (2S) -1- (N-benzyloxycarbonyl-
L-prolyl) -2- {1-hydroxy-2-[(S)
-Phenylsulfinyl] ethyl} pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-2- (phenylsulfinyl) ethyl] obtained in A) of Example 2. Pyrrolidine (6.72 g) was again subjected to medium pressure silica gel column chromatography (eluent; chloroform: methanol = 9).
8: 2) and the title compound (2.51 g),
The corresponding (R) -phenylsulfinyl derivative (2.20 g) of the title compound and a mixture of both (1.87 g) were obtained.

B) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-{[(S) -phenylsulfinyl] acetyl} pyrrolidine (2S) -1- (N-benzyloxycarbonyl- L-
Prolyl) -2- {1-hydroxy-2-[(S) -phenylsulfinyl] ethyl} pyrrolidine (600 m
g) in the same manner as in D) of Example 1
Subjected to DCC oxidation, the resulting reaction product was subjected to medium pressure silica gel column chromatography (eluent; chloroform:
Purification with methanol = 99.5: 0.5) gave the title compound (242 mg) (see Table 3).

Example 13 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-{[(R) -phenylsulfinyl]
Acetyl} pyrrolidine (Compound 13) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- {1-hydroxy-2-[(R) -phenyl) obtained in A) of Example 12 Sulfinyl] ethyl} pyrrolidine (1.00 g) was subjected to DMSO-DCC oxidation in the same manner as in D) of Example 1, and the obtained reaction product was subjected to medium-pressure silica gel column chromatography (eluent; Chloroform: methanol = 99.5: 0.
After purification in 5), the obtained oil (500 mg) was recrystallized from acetone-ether-hexane to give the title compound (300 mg) as colorless needles (see Table 4).

Example 14 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-{[(S) -4-methoxyphenylsulfinyl] acetyl} pyrrolidine (Compound 14) A) (2S) -1- (N-benzyloxycarbonyl-
L-prolyl) -2- {1-hydroxy-2-[(S)
-4-Methoxyphenylsulfinyl] ethyl} pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-2- (4- Methoxyphenylsulfinyl] ethyl} pyrrolidine (575 mg) was purified again by using medium pressure silica gel column chromatography (eluent; chloroform: methanol = 98.5: 1.5) to give the title compound (164 mg), which corresponds to the title compound. Do (R) -4
-Methoxyphenylsulfinyl derivative (221 mg) and a mixture of the both (175 mg) were obtained.

B) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-{[(S) -4-methoxyphenylsulfinyl] acetyl} pyrrolidine (2S) -1- (N-benzyl) Oxycarbonyl-L-
Prolyl) -2- {1-hydroxy-2-[(S) -4
-Methoxyphenylsulfinyl] ethyl} pyrrolidine (152 mg) was subjected to DMSO-DCC oxidation in the same manner as in Example 1 D), and the resulting reaction product was subjected to silica gel preparative thin layer chromatography (developing solvent). Chloroform: methanol = 98: 2; double development) to give the title compound (97 mg) (see Table 4).

Example 15 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-{[(R) -4-methoxyphenylsulfinyl] acetyl} pyrrolidine (Compound 15) (2S) -1- (N-benzyloxycarbonyl-L-prolyl obtained in Example 14A). ) -2- {1-hydroxy-2-[(R) -4-methoxyphenylsulfinyl] ethyl} pyrrolidine (182 mg) was subjected to DMSO-DCC oxidation in the same manner as in Example 1, D). The resulting reaction product was subjected to silica gel preparative thin layer chromatography (developing solvent; chloroform: methanol = 9).
9: 1; triple development), the title compound (134m
g) was obtained (see Table 4).

Example 16 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-{[(S) -p-tolylsulfinyl] acetyl} pyrrolidine (Compound 16) A) (2S) -1- (N-benzyloxycarbonyl-
L-prolyl) -2- {1-hydroxy-2-[(S)
-P-Tolylsulfinyl] ethyl} pyrrolidine Diisopropylamine (0.26 ml) in THF (6 m
l) 1.62 Mn-butyllithium-in the solution at -78 ° C
A hexane solution (1.12 ml) was added dropwise, and the mixture was stirred at 0 ° C for 0.5 hr. The reaction solution was cooled to -30 ° C, and (S)-
(−)-Methyl p-tolyl sulfoxide (255 m
A THF (6 ml) solution of g) was added dropwise, and the mixture was stirred at 0 ° C. for 0.5 hours. The reaction solution was cooled to -78 ° C, and a solution of known N-benzyloxycarbonyl-L-prolyl-L-prolinal (300 mg) in THF (6 ml) was added dropwise. After stirring for 0.5 hour, saturated aqueous ammonium chloride was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine,
It was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (388 mg).

B) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-{[(S) -p-tolylsulfinyl] acetyl} pyrrolidine (2S) -1- (N-benzyloxy) Carbonyl-L-
Prolyl) -2- {1-hydroxy-2-[(S) -p
-Tolylsulfinyl] ethyl} pyrrolidine (357m
g) in the same manner as in D) of Example 1
The resulting reaction product was subjected to DCC oxidation, and the resulting reaction product was subjected to medium pressure silica gel column chromatography (eluent: chloroform:
The title compound (16
2 mg) was obtained (see Table 4).

Example 17 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-{[(R) -p-tolylsulfinyl) acetyl] pyrrolidine (Compound 17) (R)-(+)-methyl p-instead of (S)-(-)-methyl p-tolyl sulfoxide. The title compound (32 mg) was obtained by the same procedure as in Example 16 using tolyl sulfoxide (43 mg) (see Table 5).

Example 18 (2S) -2-{[(S) -4-methoxyphenylsulfinyl] acetyl} -1- [N- (3-phenylpropionyl) -L-prolyl] pyrrolidine (Compound 18) A) N- (3-Phenylpropionyl) -L-proline 3-phenylpropionic acid (13.67 g) was used in place of 4-phenylbutyric acid, and the title compound (17) was prepared by the same procedure as in A) B) of Example 7. 0.36 g) was obtained.

B) N- (3-phenylpropionyl)-
L-prolyl-L-proline benzyl ester L-proline benzyl ester hydrochloride (0.98 g)
In methylene chloride (20 ml) under ice-cooling, N-methylmorpholine (0.49 ml), N- (3-phenylpropionyl) -L-proline (1.00 g) and HOB.
t (0.60 g) was added. After cooling to -25 ° C, DCC
(0.92 g) was added, and the mixture was stirred at -25 ° C to 0 ° C for 2 hr and then at room temperature for 14 hr. The reaction mixture was treated and purified in the same manner as in Example 5 A) to give the title compound (1.39 g).

C) (S)-(-)-4-Methoxyphenylmethylsulfoxide Titanium tetraisopropoxide (1.49 ml) was dissolved in methylene chloride (50 ml) in (S, S) -diethyl tartrate (1.71 ml). And water (90 μl) were added and the mixture was stirred at room temperature for 20 minutes. 1-Methoxy-4- (methylthio) benzene (0.69 ml) was added dropwise, the reaction solution was cooled to -20 ° C, and 3.07M t-butyl hydroperoxide-toluene solution (1.8 ml).
Was added dropwise and the mixture was stirred at -20 ° C for 15 hours. Water (0.9m
1) was added, and the mixture was further stirred at -20 ° C for 1 hr and then at room temperature for 1 hr. After adding a small amount of alumina, the reaction solution was suction filtered using Celite and thoroughly washed with methylene chloride. The filtrate and the washing solution were combined, 5% sodium hydroxide-saturated saline was added, and the mixture was stirred at room temperature for 1 hour. Separate the organic layer,
The extract was dried over magnesium sulfate and concentrated. The residue (730 mg) obtained by purifying the residue by silica gel column chromatography (eluent; ethyl acetate) was recrystallized from ether-pentane, and [α] _D -103 ° (c = 1.9).
The title compound (586 mg) of (8, acetone) was obtained. D) (2S) -2-{[(S) -4-methoxyphenylsulfinyl] acetyl} -1- [N- (3-phenylpropionyl) -L-prolyl] pyrrolidine diisopropylamine (0.13 ml) in THF ( 8m
l) 1.62 Mn-butyllithium-hexane solution (1.2 ml) was added dropwise to the solution at -78 ° C, and 0.5 at 0 ° C.
Stir for hours. After cooling the reaction solution to -30 ° C, (S)-
A solution of (−)-4-methoxyphenyl methyl sulfoxide (157 mg) in THF (8 ml) was added dropwise, and the temperature was 0 ° C.
It was stirred for 0.5 hour. After cooling the reaction solution to -78 ° C, N
-(3-Phenylpropionyl) -L-prolyl-L-
THF of proline benzyl ester (400 mg)
(8 ml) solution was added quickly and stirred for 0.5 hours. The reaction mixture was treated in the same manner as in Example 16 A) and the obtained reaction mixture was purified by medium pressure silica gel column chromatography (eluent: chloroform: methanol = 99: 1) to give the title compound (195 mg). Was obtained (see Table 5).

Example 19 (2S) -1- [N- (3-phenylpropionyl)-
L-prolyl] -2-{[(S) -p-tolylsulfinyl] acetyl} pyrrolidine (Compound 19) (S)-(-)-4-methoxyphenylmethylsulfoxide instead of (S)-(-)- The oily product (231 mg) obtained by the same operation as in the case of D) of Example 18 was recrystallized from hexane-ethyl acetate using methyl p-tolyl sulfoxide (142 mg) to give the title compound (160 mg) as colorless needles. Obtained (see Table 5).

Example 20 (2S) -1- [N- (3-phenylpropionyl)-
L-prolyl] -2-{[(S) -phenylsulfinyl] acetyl} pyrrolidine (compound 20) A) (S)-(-)-methyl phenyl sulfoxide 1-methoxy-4- (methylthio) benzene instead of benzene Using [alpha] _D- 125 [deg.] (C =
The title compound (4.63 g) of 1.81 and acetone) was obtained.

B) (2S) -1- [N- (3-Phenylpropionyl) -L-prolyl] -2-{[(S) -phenylsulfinyl] acetyl} pyrrolidine (S)-(-)- (S)-(−)-methylphenyl sulfoxide (129 mg) was used in place of 4-methoxyphenyl methyl sulfoxide, and the crystalline substance (202 m) obtained by the same procedure as in the case of D) of Example 18 was used.
g) was recrystallized from hexane-ethyl acetate to give the title compound (155 mg) as colorless needles (see Table 5).

Example 21 (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2-[(4-methoxyphenoxy) acetyl] pyrrolidine (Compound 21) A) (2S) -1- (t-butoxycarbonyl) -2-
[1-Hydroxy-2- (4-methoxyphenoxy) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- (1,2-epoxyethyl) pyrrolidine (prepared in A) of Example 1 4-Methoxyphenol (13.60 g) and 1M sodium methoxide-methanol solution (54.9 ml) were added to a solution of 11.70 g) in methanol (50 ml), and the mixture was stirred at 70 ° C. for 18 hours. The reaction solution was poured into saturated ammonium chloride water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (14.20 g).

B) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2- [1-hydroxy-
2- (4-Methoxyphenoxy) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- [1
4N Hydrochloric acid-dioxane (220 ml) was added to -hydroxy-2- (4-methoxyphenoxy) ethyl] pyrrolidine (14.03 g), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentrating and drying the reaction solution was added to DMF (100 ml).
And the known N-benzyloxycarbonyl-L-proline (10.
70 g) to give the title compound (11.10).
g) was obtained.

C) (2S) -1- (N-benzyloxycarbonyl-L-prolyl) -2-[(4-methoxyphenoxy) acetyl] pyrrolidine (2S) -1- (N-benzyloxycarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (4-methoxyphenoxy) ethyl] pyrrolidine (10.94 g) was subjected to DMSO-DCC oxidation in the same manner as in D) of Example 1 to give the title compound ( 10.78 g) was obtained (Table 6)
reference).

Example 22 (2S) -2- (phenoxyacetyl) -1- [N-
(3-Phenylpropionyl) -L-prolyl] pyrrolidine (Compound 22) A) (2S) -2- (1-hydroxy-2-phenoxyethyl) -1- [N- (3-phenylpropionyl)-
L-prolyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- (1-hydroxy-2-phenoxyethyl) pyrrolidine (1.20 g) prepared in A) of Example 4 was mixed with 4N hydrochloric acid-dioxane. It was dissolved in (20 ml) and stirred at room temperature for 0.5 hours. The reaction solution was concentrated and dried, and the resulting residue was added to DMF (9 m
l) and condensing with N- (3-phenylpropionyl) -L-proline (0.96 g) prepared in A) of Example 18 in the same manner as in C) of Example 1 The title compound (461 mg) was obtained.

B) (2S) -2- (phenoxyacetyl) -1- [N- (3-phenylpropionyl) -L-
Prolyl] pyrrolidine (2S) -2- (1-hydroxy-2-phenoxyethyl) -1- [N- (3-phenylpropionyl) -L-
Prolyl] pyrrolidine (425 mg) was subjected to DMSO-DCC oxidation in the same manner as in D) of Example 1,
The title compound (152 mg) was obtained (see Table 6).

Example 23 (2S) -2-[(4-methoxyphenoxy) acetyl] -1- [N- (3-phenylpropionyl) -L-
Prolyl] pyrrolidine (Compound 23) A) (2S) -2- [1-hydroxy-2- (4-methoxyphenoxy) ethyl] -1- [N- (3-phenylpropionyl) -L-prolyl] pyrrolidine Example 21A) prepared with (2S) -1- (t-butoxycarbonyl) -2- [1-hydroxy-2- (4-
Methoxyphenoxy) ethyl] pyrrolidine (455m
g) was dissolved in 4N hydrochloric acid-dioxane (7 ml) and stirred at room temperature for 0.5 hours. The residue obtained by concentrating and drying the reaction solution was dissolved in DMF (7 ml), and N- (3-) prepared in A) of Example 18 was treated in the same manner as in C) of Example 1.
Phenylpropionyl) -L-proline (335 mg)
By condensing with, the title compound (138 mg) was obtained.

B) (2S) -2-[(4-methoxyphenoxy) acetyl] -1- [N- (3-phenylpropionyl) -L-prolyl] pyrrolidine (2S) -2- [1-hydroxy- 2- (4-Methoxyphenoxy) ethyl] -1- [N- (3-phenylpropionyl) -L-prolyl] pyrrolidine (128 mg)
In the same manner as in D) of Example 1
Subjected to C oxidation to give the title compound (45 mg) (see Table 6).

Example 24 (2S) -1- (N-benzylaminocarbonyl-L-
Prolyl) -2- (phenoxyacetyl) pyrrolidine (Compound 24) A) (2S) -1- [N- (t-butoxycarbonyl)
-L-prolyl] -2- (1-hydroxy-2-phenoxyethyl) pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- (1-hydroxy-2-) prepared in A) of Example 4. Phenoxyethyl) pyrrolidine (1.93 g) was dissolved in 4N hydrochloric acid-dioxane (31 ml), and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated and dried, and the resulting residue was added to DMF (15
ml), N- (t-butoxycarbonyl) -L
-Proline (1.36g), N-methylmorpholine (0.69ml), HOBt (1.02g) and DCC
Using (1.30 g) and performing the condensation reaction in the same manner as in the case of C) in Example 1, the title compound (2.10 g) was obtained.

B) (2S) -1- (N-benzylaminocarbonyl-L-prolyl) -2- (1-hydroxy-
2-phenoxyethyl) pyrrolidine (2S) -1- [N- (t-butoxycarbonyl) -L
-Prolyl] -2- (1-hydroxy-2-phenoxyethyl) pyrrolidine (0.99 g) was dissolved in 4N hydrochloric acid-dioxane (13 ml), and the mixture was stirred at room temperature for 0.5 hr.
The reaction solution was concentrated and dried, and the resulting residue was treated with methylene chloride (1
0 ml) and N-methylmorpholine (0.27 ml) and benzyl isocyanate (0.30) under ice cooling.
ml) was sequentially added dropwise. After stirring for 1.5 hours, the reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from a mixed solution of ethyl acetate-hexane to give the title compound (0.85 g).

C) (2S) -1- (N-benzylaminocarbonyl-L-prolyl) -2- (phenoxyacetyl) pyrrolidine (2S) -1- (N-benzylaminocarbonyl-L-
Prolyl) -2- (1-hydroxy-2-phenoxyethyl) pyrrolidine (798 mg) was subjected to DMSO-DCC oxidation in the same manner as in the case of D) of Example 1, and after treatment, recrystallized from an ethyl acetate-hexane mixed solution. The title compound (42
7 mg) was obtained (see Table 6).

Example 25 (2S) -1- (N-benzylaminocarbonyl-L-
Prolyl) -2- (4-methoxyphenoxyacetyl)
Pyrrolidine (Compound 25) A) (2S) -1- [N- (t-butoxycarbonyl)
-L-prolyl] -2- [1-hydroxy-2- (4-
(Methoxyphenoxy) ethyl] pyrrolidine (2S) -1- (t-butoxycarbonyl) -2- [1-hydroxy-2- (4-) prepared in A) of Example 21.
Methoxyphenoxy) ethyl] pyrrolidine (1.57
g) was dissolved in 4N hydrochloric acid-dioxane (23 ml) and stirred at room temperature for 1 hour. The residue obtained by concentrating and drying the reaction solution was dissolved in DMF (15 ml), and N- (t-butoxycarbonyl) -L-proline (1.00 g), N-methylmorpholine (0.51 ml) and HOBt (0 (75 g)
And DCC (0.96 g) were subjected to the condensation reaction in the same manner as in the case of C) in Example 1 to give the title compound (1.
41 g) was obtained.

B) (2S) -1- (N-benzylaminocarbonyl-L-prolyl) -2- [1-hydroxy-
2- (4-Methoxyphenoxy) ethyl] pyrrolidine (2S) -1- [N- (t-butoxycarbonyl) -L
-Prolyl] -2- [1-hydroxy-2- (4-methoxyphenoxy) ethyl] pyrrolidine (722 mg)
In the same manner as in Example 24 B).
After dioxane treatment, benzyl isocyanate (0.21
ml) to give crystals of the title compound (596 mg).

C) (2S) -1- (N-benzylaminocarbonyl-L-brolyl) -2- (4-methoxyphenoxyacetyl) pyrrolidine (2S) -1- (N-benzylaminocarbonyl-L-
Prolyl) -2- [1-hydroxy-2- (4-methoxyphenoxy) ethyl] pyrrolidine (557 mg) as D
It was dissolved in a mixed solution of MSO (3 ml), benzene (1.5 ml) and triethylamine (0.6 ml), and sulfur trioxide-pyridine complex (0.52 g) was added under ice cooling. 5-
After stirring at 10 ° C for 1 hour, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from a mixed solution of ethyl acetate-hexane to give the title compound (374 mg) (see Table 7).

Example 26 (2S) -1- (N-benzylaminocarbonyl-L-
Prolyl) -2-{[(S) -4-methoxyphenylsulfinyl] acetyl} pyrrolidine (Compound 26) A) N- (t-butoxycarbonyl) -L-prolyl-
L-proline benzyl ester L-proline benzyl ester hydrochloride (3.37 g)
In methylene chloride suspension (60 ml) under ice-cooling, N-methylmorpholine (1.54 ml), N- (t-butoxycarbonyl) -L-proline (3.00 g), HOBt.
(2.08 g) and water-soluble carbodiimide hydrochloride (2.
95 g) was sequentially added and stirred for 1 hour. 17 more at room temperature
After stirring for an hour, the reaction solution was poured into ethyl acetate, 1N hydrochloric acid,
The extract was washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Silica gel column chromatography of the residue (eluent: hexane-ethyl acetate)
The title compound (5.00 g) was obtained.

B) N-benzylaminocarbonyl-L-
Prolyl-L-proline benzyl ester N- (t-butoxycarbonyl) -L-prolyl-L-
Proline benzyl ester (3.60 g) was used in Example 24
In the same manner as in B) of 4), the mixture was treated with 4N hydrochloric acid-dioxane and then reacted with benzyl isocyanate (1.2 ml) to obtain crystals of the title compound (2.98 g).

C) (2S) -1- (N-benzylaminocarbonyl-L-prolyl) -2-{[(S) -4-methoxyphenylsulfinyl] acetyl} pyrrolidine N-benzylaminocarbonyl-L-prolyl- L-proline benzyl ester (2.00 g) and Example 18
(S)-(−)-4-methoxyphenylmethyl sulfoxide (780 mg) prepared in C) of Example 18 was used to carry out the same reaction as in Example 18 D) to give the title compound as colorless needles. (629 mg) was obtained (see Table 7).

Example 27 (2S) -1- [N- (4-Methoxybenzylaminocarbonyl) -L-prolyl] -2-{[(S) -4-methoxyphenylsulfinyl] acetyl} pyrrolidine (Compound 27) A) N- (4-methoxybenzylaminocarbonyl)-
L-Prolyl-L-proline benzyl ester Trichloromethyl chloroformate (0.28 ml) in THF
To a solution (40 ml) at -20 ° C, 4-methoxybenzylamine (0.61 ml) and triethylamine (0.
A THF solution (20 ml) of 65 ml) was added dropwise over 10 minutes. After stirring for 1 hour, N- prepared in Example 26 A)
A methylene chloride solution (20 ml) of L-prolyl-L-proline benzyl ester hydrochloride (1.57 g) obtained by treating (t-butoxycarbonyl) -L-prolyl-L-proline benzyl ester with 4N hydrochloric acid-dioxane and Triethylamine (1.3 ml) was sequentially added dropwise and stirred for 0.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (1.34 g).

B) (2S) -1- [N- (4-methoxybenzylaminocarbonyl) -L-prolyl] -2-
{[(S) -4-Methoxyphenylsulfinyl] acetyl} pyrrolidine N- (4-methoxybenzylaminocarbonyl) -L-
Prolyl-L-proline benzyl ester (1.30
g) and (S)-(-)-4 prepared in C) of Example 18.
-Methoxyphenylmethyl sulfoxide (480 mg)
Was used and the same reaction as in the case of D) of Example 18 was performed to give the title compound (460 mg) as colorless needles (see Table 7).

Example 28 (2S) -1- [N- (4-Methoxybenzylaminocarbonyl) -L-prolyl] -2- (4-methoxyphenoxyacetyl) pyrrolidine (Compound 28) A) (2S) -2 -[1-Hydroxy-2- (4-methoxyphenoxy) ethyl] -1- [N- (4-methoxybenzylaminocarbonyl) -L-prolyl] pyridine trichloromethyl chloroformate (0.20 ml), 4-methoxybenzyl (2S) -1- [N- (t-butoxycarbonyl) -L-prolyl] -2- [1-hydroxy prepared with amine (449 mg), triethylamine (0.45 ml + 0.89 ml) and A of Example 25). −
2- (4-Methoxyphenoxy) ethyl] pyrrolidine was obtained by treating 4N hydrochloric acid-dioxane with (2S) -2- [1.
-Hydroxy-2- (4-methoxyphenoxy) ethyl] -1- (L-prolyl) pyrrolidine hydrochloride (1.1
The title compound (661 mg) was obtained by the same reaction as in Example 27 A) using 8 g).

B) (2S) -1- [N- (4-methoxybenzylaminocarbonyl) -L-prolyl] -2-
(4-Methoxyphenoxyacetyl) pyrrolidine (2S) -2- [1-hydroxy-2- (4-methoxyphenoxy) ethyl] -1- [N- (4-methoxybenzylaminocarbonyl) -L-prolyl] The title compound (387) in the form of colorless needles was obtained by oxidizing pyrrolidine (614 mg) with sulfur trioxide-pyridine complex (0.37 g) in the same manner as in the case of C) in Example 25.
mg) was obtained (see Table 7). The physicochemical properties of these compounds 1 to 28 are shown in Tables 1 to 7.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7] Further, the present invention is not limited to these examples, and for example, the compounds 29 to 4 shown in Table 8 can be used.
4 also belongs to the present invention.

[Table 8]

Next, the prolyl endopeptidase inhibitory activity and the inhibitory activity against various proteolytic enzymes in the in vitro system of the proline derivative represented by the general formula [1] according to the present invention were tested. Test Example 1 Prolyl endopeptidase inhibitory activity 0.1 M potassium-sodium phosphate buffer (pH 7.
0) 2675 μl, 100 μl of 0.1 M potassium-sodium phosphate buffer solution (pH 7.0) of the compound of the present invention
And a solution of prolyl endopeptidase extracted from rat brain in 25 mM sodium phosphate buffer (123 units / 1, pH 6.8, 1 mM dithiothreitol and 0.
Contains 5 mM EDTA. J. Neurochem. ，
35 , 527 (1980) was used) 10
0 μl of the mixture was preincubated for 30 minutes at 30 ° C. To this, 125 μl of a 0.1 M potassium phosphate-sodium phosphate buffer solution (pH 7.0) of 0.2 mM 7- (N-succinyl-glycyl-prolyl) -4-methylcoumarinamide (manufactured by Peptide Laboratories, Inc.) was added. In addition, the mixture was incubated at 30 ° C for 1 hour. The reaction solution was immersed in ice (0 ° C.) to stop the reaction, and after 10 minutes, the fluorescence intensity (a at excitation wavelength 370 nm and fluorescence wavelength 440 nm) (a
₁ ) was measured. At the same time, in the above system, an experiment using 25 mM sodium phosphate buffer (containing pH 6.8, 1 mM dithiothreitol and 0.5 mM EDTA) instead of the prolyl endopeptidase solution, and the substitution of the compound solution of the present invention Experiment using 0.1 M potassium-sodium phosphate buffer solution (pH 7.0) was performed for
Fluorescence intensities a ₂ and a ₃ were measured (protein nucleic acid enzyme,
29 , 127 (1984)). The prolyl endopeptidase inhibition rate was calculated by the equation 1, and the concentration required for 50% inhibition (IC ₅₀ ) was determined using a semilogarithmic graph. The test results are shown in Table 9.

[Equation 1]

[Table 9] As is clear from the results of this test, it was confirmed that the compound of the present invention has an excellent inhibitory activity against prolyl endopeptidase.

Test Example 2 Inhibitory activity against various proteolytic enzymes The compounds of the present invention were tested for specificity of the inhibitory activity against various proteolytic enzymes at a predetermined concentration. It was found to specifically inhibit peptidases.

[Table 10] The method for measuring the inhibitory activity of various proteolytic enzymes excluding prolyl endopeptidase and the method for calculating the inhibition rate are as follows.

Measurement of Trypsin Inhibitory Activity In this test, 50 mM Tris-HCl buffer (pH 8.0) was used as the measurement buffer. Same buffer 8
0.02 μM of 50 μl, 50 μl of the same buffer solution of the compound of the present invention and trypsin (derived from bovine pancreas, manufactured by Sigma)
To a mixed solution of 50 μl of the same buffer solution, 50 μl of a 200 μM same-buffer solution of 7- (prolyl-phenylalanyl-arginyl) -4-methylcoumarinamide (manufactured by Peptide Laboratory Co., Ltd.) was added, and the mixture was added at 30 ° C. at 1 ° C. Incubated for hours. The reaction solution was immersed in ice (0 ° C.) to stop the reaction, and 1 hour later, the fluorescence intensity (b ₁ ) at an excitation wavelength of 370 nm and a fluorescence wavelength of 440 nm was measured. At the same time, in the above system, an experiment using the same buffer solution instead of the trypsin solution, and an experiment using the same buffer solution instead of the compound solution of the present invention,
Similarly, the fluorescence intensities (b ₂ ) and (b ₃ ) were measured.

Measurement of Chymotrypsin Inhibitory Activity 50 mM Tris-HCl buffer (pH
8.0), 0.2 μM chymotrypsin (derived from bovine pancreas, Sigma) buffer solution as an enzyme solution, and 7- (N-succinyl-leucyl-leucyl-valyl-tyrosyl) -4- as a substrate solution. Using a 200 μM buffer solution of methylcoumarinamide (manufactured by Peptide Research Co., Ltd.) in the same manner as above, the fluorescence intensities c ₁ , c
₂ and c ₃ were measured.

● Measurement of leucine aminopeptidase inhibitory activity 50 mM Tris-HCl buffer (pH
8.0), a 0.2 μM buffer solution of leucine aminopeptidase (derived from pig kidney, manufactured by Sigma) as an enzyme solution, and as a substrate solution, 7-leucyl-4-methylcoumarinamide (Peptide Research Institute, Inc.) (Manufactured by K.K.) was used, and the fluorescence intensities d ₁ , d ₂ and d ₃ were measured in exactly the same manner as above.

Measurement of Elastase Inhibitory Activity 1 mM Tris-HCl buffer (pH
8.5) was added with 0.2 μM buffer solution of elastase (derived from pig pancreas, manufactured by Sigma) as an enzyme solution and 7- (N-succinyl-alanyl-prolyl-) as a substrate solution.
Using a 200 μM buffer solution of alanyl) -4-methylcoumarinamide (manufactured by Peptide Research Co., Ltd.), fluorescence intensities e ₁ , e ₂ and e ₃ were measured in exactly the same manner as above.

Measurement of Cathepsin B Inhibitory Activity 100 mM sodium phosphate buffer (pH 6.0; containing 1.33 mM EDTA.Na ₂ ) was used as a measurement buffer, and cathepsin B (derived from bovine spleen as an enzyme solution,
Sigma's 0.02 μM buffer solution was used as a substrate solution of 7- (N-benzyloxycarbonyl-phenylalanyl-arginyl) -4-methylcoumarinamide (manufactured by Peptide Institute Co., Ltd.) at 200 μM. Using a buffer solution, the fluorescence intensities f ₁ and f were measured in the same manner as above.
₂ and f ₃ were measured. Using the fluorescence intensities x ₁ , x ₂ and x ₃ (x represents b, c, d, e and f) thus measured, the inhibition rate against various proteolytic enzymes was calculated by
Calculated by

[Equation 2]

[0092]

The novel proline derivative represented by the above general formula [1] according to the present invention has a very strong inhibitory activity against prolyl endopeptidase, but it has trypsin, chymotrypsin, leucine aminopeptidase, elastase, It has been observed that it has no effect on proteases such as cathepsin B or exhibits only extremely weak inhibitory activity. Therefore, it is involved in hormones and neurotransmitters in the brain containing proline residues, learning and memory. Is considered to be, for example, decomposition of TRH, substance P, neurotensin, vasopressin, etc.,
It is considered to be a compound that specifically suppresses inactivation. Therefore, the compound of the present invention can be expected to make an effective contribution to the improvement of symptoms of various diseases mediated by hormones and neurotransmitters, and as an anti-dementia drug or an anti-amnestic agent that directly acts on the core symptoms of dementia, dementia and Prevention of amnesia and /
Or it can be used for therapy.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Ituro Uchida 6-2 Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Shoei Hoshino, Inspector, Pharmaceutical Research Institute

Claims (1)

[Claims] 1. A general formula [1]: [In the formula, B is W is Or CH ₃ — (wherein R ² represents a hydrogen atom, a halogen atom or a lower alkoxy group), and X is —S—, —S.
_{O -, - SO 2 -,} - O- or -NH- and, R represents ## STR4 ## Or a lower alkyl group (wherein 1 is an integer of 0 to 3,
Y and Z are the same or different and each is a hydrogen atom, a halogen atom,
It means a lower alkyl group which may be substituted with a fluorine atom, an amino group, a nitro group, a hydroxyl group or a lower alkoxy group.
Further, Y and Z may be combined with each other to form a saturated or unsaturated 5- and 6-membered ring), and n is an integer of 1 to 6].